Alport alloantibodies but not Goodpasture autoantibodies induce murine glomerulonephritis: protection by quinary crosslinks locking cryptic α3(IV) collagen autoepitopes in vivo.
Alport alloantibodies but not Goodpasture autoantibodies induce murine glomerulonephritis: protection by quinary crosslinks locking cryptic α3(IV) collagen autoepitopes in vivo.
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DOI：
10.4049/jimmunol.1001152
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发表时间：
2010-09-15
期刊：
影响因子：
--
通讯作者：
Borza DB
中科院分区：
文献类型：
--
作者：
Luo W;Wang XP;Kashtan CE;Borza DB
肾小球基底膜中α-3-α-4-α-5(IV)胶原的非胶原区(Nc1)是Good及ure自身抗体或Alport移植后肾炎同种抗体介导的快速进行性肾小球肾炎的靶点。由于α3α4α5NC1六聚体组装后自身表位而不是同种表位变得隐蔽，我们研究了B细胞表位在体内的可及性如何影响被动免疫的小鼠肾小球肾炎的发生。Alport同种异体抗体在体外与天然小鼠α3α4α5NC1六聚体结合，在体内沿着小鼠的基底膜线性沉积，在Fcgr2b−/−小鼠中引起新月体肾炎，易受抗体介导的炎症的影响。Good及ure自身抗体在体外能与小鼠α3Nc1单体和二聚体结合，但不能与天然的α3α4α5NC1六聚体结合，在体内既不能与小鼠肾小球系膜结合，也不能诱发实验性肾小球肾炎。这是由于五元NC1交联键，最近被确定为磺胺键，它全面锁定了小鼠GBM中神秘的Good及ure自身表位。相比之下，非交联型α3NC1亚单位被确定为Good及ure自身抗体在松鼠猴的基底膜中的天然目标，而松鼠猴是一种易患Good及ure自身抗体介导的肾炎的物种。因此，组织中B细胞自身表位的隐蔽性使自身免疫性疾病的潜在致病自身抗体脱钩。α3α4α5NC1六聚体的交联代表了一种新的机制，通过对自身抗原的翻译后修饰来避免自身抗体结合和随后的组织损伤。
The noncollagenous (NC1) domains of α3α4α5(IV) collagen in the glomerular basement membrane (GBM) are targets of Goodpasture autoantibodies or Alport post-transplant nephritis alloantibodies mediating rapidly progressive glomerulonephritis. Because the autoepitopes but not the alloepitopes become cryptic upon assembly of α3α4α5NC1 hexamers, we investigated how the accessibility of B cell epitopes in vivo influences the development of glomerulonephritis in mice passively immunized with human anti-GBM antibodies. Alport alloantibodies, which bound to native murine α3α4α5NC1 hexamers in vitro, deposited linearly along the mouse GBM in vivo, eliciting crescentic glomerulonephritis in Fcgr2b−/− mice susceptible to antibody-mediated inflammation. Goodpasture autoantibodies, which bound to murine α3NC1 monomer and dimer subunits but not to native α3α4α5NC1 hexamers in vitro, neither bound to the mouse GBM in vivo nor induced experimental glomerulonephritis. This was due to quinary NC1 cross-links, recently identified as sulfilimine bonds, which comprehensively locked the cryptic Goodpasture autoepitopes in the mouse GBM. In contrast, non-crosslinked α3NC1 subunits were identified as a native target of Goodpasture autoantibodies in the GBM of squirrel monkeys—a species susceptible to Goodpasture autoantibody-mediated nephritis. Thus, crypticity of B cell autoepitopes in tissues uncouples potentially pathogenic autoantibodies from autoimmune disease. Crosslinking of α3α4α5NC1 hexamers represents a novel mechanism averting autoantibody binding and subsequent tissue injury by post-translational modifications of an autoantigen.
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